Variant Reclassification Analysis Report

Summary Statistics
Gene & Variant Landscape
Classification Flow & Timing
Reasons for Reclassification
Submitter Dynamics
Detailed Variant Table
Methods & Assumptions

Summary Statistics

Total Variants

P→B Variants

Genes with P→B

Median Time to Benigning

71.1 mo

Inter-lab Flips

100.0%

Top Reason

Other/Unknown

Gene & Variant Landscape

Distribution of P→B reclassifications across genes and their characteristics.

Top Genes by P→B Variant Count

Genes with the highest number of variants reclassified from pathogenic to benign.

Gene Landscape: Count vs Time to Benigning

Bubble size represents median time to reclassification. Minimum size applied for visibility.

Classification Flow & Timing

Temporal patterns in variant reclassifications.

Classification Flow Diagram

Movement from pathogenic to benign classifications, split by inter-lab vs intra-lab changes.

Reclassification Timeline

Temporal distribution of initial P/LP and subsequent B/LB classifications.

Reasons for Reclassification

Inferred reasons driving P→B reclassifications based on ACMG evidence codes.

Primary Reasons for Reclassification

Distribution of reason categories across P→B variants.

Reason Distribution by Submitter

Heatmap showing which submitters contribute to each reclassification reason.

Submitter Dynamics

Analysis of submitter patterns in reclassifications.

Top Submitters on Benign Side

Laboratories most frequently submitting benign classifications for P→B variants.

Inter-lab vs Intra-lab Reclassifications

Proportion of reclassifications within same vs different laboratories (excludes cases with missing submitter data).

Detailed Variant Table

Complete list of all P→B variants with classification details and inferred reclassification reasons.

Showing all 21 P→B variants sorted by gene and time to benigning. Table is scrollable. The 'inferred_reasons' column shows the likely drivers of reclassification based on ACMG evidence changes.

gene	variant	type	first_plp_date	first_blb_date	first_plp_submitter	first_blb_submitter	time_to_benign_months	interlab	plp_codes	blb_codes	inferred_reasons
BRCA2	NM_000059.4(BRCA2):c.8187G>T (p.Lys2729Asn)	missense	2002-07-26	2011-03-14	OMIM	Sharing Clinical Reports Project (SCRP)	103.6	True			Other/Unknown
BRCA2	NM_000059.4(BRCA2):c.7879A>T (p.Ile2627Phe)	missense	2012-03-11	2019-09-01	Sharing Clinical Reports Project (SCRP)	King Laboratory, University of Washington	89.7	True			Other/Unknown
BRCA2	NM_000059.4(BRCA2):c.891_899delinsGATACTTAG (p.Thr298_Val300delinsIleLeuArg)	missense	2017-04-20	2023-03-23	Department of Pathology and Molecular Medicine, Queen's University	University of Washington Department of Laboratory Medicine, University of Washington	71.1	True	PM1,PM2,PP4	BP1	Guideline/model change
BRCA2	NM_000059.4(BRCA2):c.8851G>T (p.Ala2951Ser)	missense	2020-04-08	2025-05-16	Center of Medical Genetics and Primary Health Care	Ambry Genetics	61.2	True	PM1,PM2,PP3,PP4	BP2,BP4,BP5,BP7,BS1,BS2,BS3,BS4	Population frequency, New benign functional evidence, Computational shift
BRCA2	NM_000059.4(BRCA2):c.2623G>C (p.Val875Leu)	missense	2020-04-08	2023-03-23	Center of Medical Genetics and Primary Health Care	University of Washington Department of Laboratory Medicine, University of Washington	35.4	True	BP4,PM1,PM2,PP1,PS1	BP4,BS1	Population frequency, Guideline/model change
COL4A5	NM_033380.3(COL4A5):c.2692A>G (p.Met898Val)	missense	2019-02-14	2019-06-15	Yale Center for Mendelian Genomics, Yale University	PreventionGenetics, part of Exact Sciences	4.0	True			Other/Unknown
HNF1A	NM_000545.8(HNF1A):c.1748G>A (p.Arg583Gln)	missense	2002-10-01	2016-10-27	OMIM	Ambry Genetics	168.9	True		BP1,BP4,BP5,BS1,BS2,BS3,BS4	Population frequency, New benign functional evidence
HNF1A	NM_000545.8(HNF1A):c.92G>A (p.Gly31Asp)	missense	2005-03-01	2017-03-01	OMIM	GeneDx	144.0	True		BP4,BS1	Population frequency
NPHS1	NM_004646.4(NPHS1):c.559G>A (p.Val187Met)	Missense variant in extracellular domain of nephrin protein	2018-09-16	2023-03-02	Gharavi Laboratory, Columbia University	Labcorp Genetics (formerly Invitae), Labcorp	53.5	True	PP4		Other/Unknown
NPHS1	NM_004646.4(NPHS1):c.559G>A (p.Val187Met)	missense	2018-09-16	2023-03-02	Gharavi Laboratory, Columbia University	Labcorp Genetics (formerly Invitae), Labcorp	53.5	True	PM2,PP3,PP4	BA1,BP4,BS1	Population frequency (BA1 threshold), Computational shift, Guideline/model change
NPHS1	NM_004646.4(NPHS1):c.559G>A (p.Val187Met)	missense	2018-09-16	2023-03-02	Gharavi Laboratory, Columbia University	Labcorp Genetics (formerly Invitae), Labcorp	53.5	True			Other/Unknown
NPHS2	NM_014625.4(NPHS2):c.59C>T (p.Pro20Leu)	missense	2003-05-01	2016-03-04	OMIM	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	154.1	True	PM1,PM2,PP1,PS4	BP4,BP6,BS1,BS2	Population frequency
NPHS2	NM_014625.4(NPHS2):c.59C>T (p.Pro20Leu)	missense	2003-05-01	2016-03-04	OMIM	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	154.1	True		BS1,BS2	Population frequency
PAX2	NM_000278.5(PAX2):c.1058A>C (p.Gln353Pro)	missense		2020-01-22	Precision Medicine Center, Zhengzhou University	PreventionGenetics, part of Exact Sciences	NaN	True	PM1,PP1,PP3,PP4,PP5	BP4,BP7,BS1	Population frequency, Computational shift, Guideline/model change
PAX2	NM_000278.5(PAX2):c.1058A>C (p.Gln353Pro)	missense		2020-01-22	Precision Medicine Center, Zhengzhou University	PreventionGenetics, part of Exact Sciences	NaN	True	PM1,PP1,PP3,PP4,PP5		Other/Unknown
PKD1	NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu)	missense	1999-07-01	2019-04-19	OMIM	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	237.6	True			Other/Unknown
PKD1	NM_001009944.3(PKD1):c.971G>T (p.Arg324Leu)	missense	1999-07-01	2019-04-19	OMIM	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	237.6	True			Other/Unknown
RET	NM_020975.6(RET):c.2372A>T (p.Tyr791Phe)	missense	2006-08-28	2012-07-13	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	70.5	True			Other/Unknown
SCNN1G	NM_001039.4(SCNN1G):c.589G>A (p.Glu197Lys)	missense	2008-05-28	2017-04-27	OMIM	Illumina Laboratory Services, Illumina	107.0	True	PP1,PS3	BP4,BS1	Population frequency
TSC2	NM_000548.5(TSC2):c.4639G>A (p.Val1547Ile)	missense	2017-04-11	2021-01-19	OMIM	Ambry Genetics	45.3	True	PM2,PP3,PS3	BP1,BP4,BP5,BS1,BS2,BS3,BS4	Population frequency, Functional (benign evidence), Computational shift
TSC2	NM_000548.5(TSC2):c.1081C>G (p.Leu361Val)	missense	2018-08-01	2020-03-20	Liping Wei Laboratory, Peking University	GeneDx	19.6	True		BP4,BS4	Guideline/model change

Methods & Assumptions

P→B Detection: Variants with any submission in Pathogenic/Likely pathogenic AND any submission in Benign/Likely benign groups.
Evidence Bucket Mapping: ACMG criteria grouped into functional categories:
- Population frequency: BA1, BS1
- Computational predictions: PP3, BP4
- Segregation: PP1, BS4
- Functional studies: PS3, BS3
- De novo / family: PS2, PM6
- Allelic / co-occurrence: PM3, BP2, BP5
- Null/LOF: PVS1
- Case-control: PS4
- Reputable source / clinical assertions: PP5, BP6
- Variant type vs disease mechanism: BP1
- Other benign mechanisms: BS2, BP7
Reason Inference Logic:
- Population frequency (BA1 threshold): BA1 appears on benign side but not on P/LP side (strongest evidence)
- Population frequency: BS1 appears on benign side but not on P/LP side
- Functional (benign evidence): BS3 appears on benign side while PS3 was on P/LP side
- New benign functional evidence: BS3 appears with no prior functional evidence (PS3 or BS3)
- Computational shift: BP4 newly appears on benign side to counter PP3 from P/LP side
- Segregation: BS4 newly appears on benign side to counter PP1 from P/LP side
- Guideline/model change: Different guidelines AND different evidence buckets
Data Quality Checks:
- Classification matching: Case-insensitive with whitespace trimming
- ACMG code normalization: Handles suffixes (_supporting), strength modifiers, and parenthetical notes
- Timeline validation: First B/LB must occur on or after first P/LP when dates available
- Date formatting: Standardized to YYYY-MM-DD for display
- Missing submitters: Treated as "Unknown" for consistency
Date Parsing: Multiple formats supported (MM/DD/YYYY, YYYY-MM-DD, textual months). Missing dates handled gracefully.
Timeline Selection: First B/LB date is the earliest benign classification occurring on or after the first P/LP date (when P/LP date exists).
Exclusions: Variants with exclude=true flag were omitted from all analyses.
Inter-lab vs Intra-lab: Based on whether P/LP and B/LB submitters differ. Cases with missing submitters are marked as "Unknown".
Time to Benigning: Calculated as days between first P/LP and first B/LB dates (B/LB must be on or after P/LP).
Evidence Precedence: Explicit assertion_criteria used first; assertion_criteria_speculated used as fallback.

Variant Reclassification Analysis

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